The role of CREB in stress-induced reinstatement

CREB ​​在应激诱导恢复中的作用

• 批准号: 8232158
• 负责人: LISA A BRIAND
• 金额: $ 5.17万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-03-01 至 2013-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8232158
• 关键词: Acute; Amygdaloid structure; Animal Model; Animals; Behavior; Behavioral; Brain region; Cells; Chronic stress; Cocaine; Cocaine Dependence; Corticotropin-Releasing Hormone; Cyclic AMP-Responsive DNA-Binding Protein; Exhibits; Experimental Designs; Exposure to; Gene Activation; Goals; Grant; Hippocampus (Brain); Human; Hypothalamic structure; Immunohistochemistry; Infusion procedures; Injection of therapeutic agent; Label; Lead; Molecular; Mus; Mutant Strains Mice; Neurobiology; Neurons; Nucleus Accumbens; Pattern; Pharmaceutical Preparations; Pharmacological Treatment; Prefrontal Cortex; Public Health; Relapse; Research; Resistance; Rewards; Rodent Model; Role; Stimulus; Stress; Structure of terminal stria nuclei of preoptic region; Swimming; System; Ventral Tegmental Area; Work; acute stress; classical conditioning; cohort; coping; drug discovery; drug relapse; experience; mutant; neural circuit; neurochemistry; new therapeutic target; preference; response; restraint; restraint stress; stressor

DESCRIPTION (provided by applicant): Although cocaine addiction is a major public health problem, currently no effective pharmacological treatment options exist. With relapse rates estimated at around 40-60%, developing a better understanding of the mechanisms underlying relapse could provide us with the means to develop better treatment options. Stress has been shown to elicit relapse to cocaine seeking in human addicts and reinstatement of drug seeking in animals models; however, the molecular mechanisms by which stress leads to relapse is unknown. Recent work in our lab has demonstrated that cAMP response element binding protein (CREB) is necessary for stress- but not cocaine-induced reinstatement of conditioned place preference using mice with a constitutive deletion of CREB. Currently, it is unclear which aspects of the neural circuitry depend on CREB to drive stress-induced reinstatement of cocaine seeking. Utilizing behavioral, immunohistochemical, and neuropharmacological approaches, this grant aims to examine the role of CREB in stress-induced reinstatement of cocaine conditioned place preference. Initially, we will examine the role of behavioral coping strategies in response to stress will be examined by examining the ability of stressors that do not engage altered behavioral responding in CREB deficient mice to lead to resinstatement of conditioned reward. Additionally, we will examine differences between both naive and cocaine-experienced wildtype and CREB deficient mice in the ability of stress to engage neurobiological circuitry implicated in stress-induced reinstatement. Finally, interactions between CREB and corticotropin-releasing factor (CRF) will be elucidated by local infusions of CRF into the bed nucleus of the stria terminalis (BNST) and the ventral tegmental area (VTA) prior to reinstatement. The goal of this research is to gain a better understanding of how stressful experiences can lead to drug relapse. By investigating the role of CREB in both the behavioral responses to stress as well as the molecular mechanisms underlying the interactions between stress and drug seeking we can identify new therapeutic targets for drug discovery

描述(由申请人提供)：尽管可卡因成瘾是一个主要的公共卫生问题，但目前还没有有效的药物治疗选择。由于复发率估计在40%-60%左右，更好地了解复发的潜在机制可以为我们提供开发更好的治疗方案的手段。已有研究表明，应激可导致人类吸毒者复发，并在动物模型中恢复寻药行为；然而，应激导致复发的分子机制尚不清楚。我们实验室最近的工作证明，cAMP反应元件结合蛋白(CREB)对于应激-而不是可卡因诱导的条件性位置偏爱的恢复是必要的，使用CREB结构性缺失的小鼠。目前，尚不清楚神经电路的哪些方面依赖CREB来驱动应激诱导的可卡因寻求的恢复。利用行为学、免疫组织化学和神经药理学方法，本研究旨在研究CREB在应激诱导的可卡因条件性位置偏爱恢复中的作用。首先，我们将通过检测CREB缺陷小鼠中不参与改变行为反应的应激源导致条件性奖赏重新陈述的能力来检验行为应对策略在应对压力中的作用。此外，我们将检查幼稚和可卡因经验的野生型和CREB缺陷小鼠在应激能力方面的差异，参与应激诱导的恢复的神经生物回路。最后，CREB和促肾上腺皮质激素释放因子(CRF)之间的相互作用将通过在恢复前将CRF局部注入终纹床核(BNST)和腹侧被盖区(VTA)来阐明。这项研究的目的是更好地了解压力经历如何导致药物复发。通过研究CREB在应激行为反应中的作用以及应激和药物寻求之间相互作用的分子机制，我们可以为药物发现寻找新的治疗靶点